PDT is an experimental cancer treatment modality under investigation as an alternative treatment for the local control of drug- and radiation-resistant tumors. It requires the combination in tumor target cells of a photosensitive compound, activating light and molecular oxygen. Excited singlet-state photosensitizer undergoes transition to a triplet-state which can react with molecular oxygen to produce singlet oxygen, the putative cytotoxin for PDT. Singlet oxygen is a highly reactive form of oxygen which can react with several biomolecules.
In clinical practice, a patient undergoing PDT receives an intravenous injection of the photosensitizing compound and twenty-four to seventy-two hours later the tumor is exposed to light of appropriate wavelength, e.g., from a dye laser directed through optical fibers to illuminate tissue through diffusing fibers or lens. Dosimetry and method of light delivery are dependent upon the size of the tumor and its location.
Monoamides of an aminocarboxylic acid and a tetrapyrrole, including pheophorbide a, bacteriopheophorbide a and pyropheophorbide a, have been disclosed for use in PDT and photodiagnosis of tumors. See, for example, U.S. Pat. No. 4,977,177 to J. Bommer and B. Burnham.
Most of the early PDT studies have been performed with hematoporphyrin and hematoporphyrin derivatives. Photofrin.RTM., one of the photosensitizing compounds currently in clinical use for PDT, consists of a mixture of monomer, polymer and aggregate forms of various porphyrins. It has taken several years of research to determine the cellular uptake, the pharmacokinetics and the biological effectiveness of the different molecular components within this photsensitizing preparation.
The clinical experience to date with porphyrin derivatives has not been entirely satisfactory. It has been found that porphyrin derivatives are metabolized and cleared from the patient's system relatively slowly. Consequently, the clinical use of such photosensitizers has been marked by rather severe cutaneous phototoxicity, requiring patients to remain protected from sunlight for periods of up to 4-6 weeks. Furthermore, the tissue penetrating effect of the porphyrin derivatives previously tested has been suboptimal, rendering the use of such compounds impractical for the treatment of relatively large tumors.
Because of their retention by, and destructive effect on cancer cells, the use of photosensitizing compounds in PDT continues to be an area of active investigation. However, a need exists for new photosensitizing agents in the form of single compounds of well defined structure, which produce singlet oxygen at high yield when activated by light of wavelength greater than 630 nm and which exhibit reduced normal tissue phototoxicity and superior tissue penetration, so as to overcome the above-noted drawbacks in the use of photosensitizing compounds reported to date.